This application is to renew R01 CA114456, an adjunct biomarker study to R01 CA98286, a multi-center, randomized, double-blind, placebo-controlled clinical trial (n = 1,964) to test the efficacy of supplemental calcium 1,200 mg/day and/or vitamin D3 1,000 IU/day against sporadic colorectal adenoma recurrence. The biomarker study tests whether these interventions can also normalize a panel of immunohistochemically (IHC) detected colon tissue biomarkers of risk for colorectal cancer, and whether such modulation predicts adenoma recurrence. There is strong biological plausibility and animal experimental evidence for protection against colorectal cancer by calcium and vitamin D, calcium significantly reduced adenoma recurrence in a large clinical trial, and the observational literature strongly supports protection from vitamin D. Yet, the effects of calcium and vitamin D, individually or jointly, on the normal human colorectal epithelium remain unknown, and there are currently no generally accepted pre-neoplastic biomarkers of risk for colorectal cancer. Based on advances in understanding the molecular basis of colorectal cancer, we developed a panel of IHC-detected biomarkers that provides molecular phenotyping of the normal-appearing colorectal epithelium: 1) the expression of genes involved in the normal structure and function of the colorectal epithelium that have been found to be altered early in the two major colorectal carcinogenesis pathways (APC, -catenin, E-cadherin, MSH2), 2) cell cycle events in colorectal epithelial crypt cells (proliferation: Mib-1;differentiation: p21; apoptosis inhibition and promotion: bcl-2, bax), and 3) autocrine/paracrine growth promotion and inhibition factors (TGF , TGF 1), and investigated the biomarkers" responses to calcium and/or vitamin D in a preliminary chemoprevention trial. In the current biomarker adjunct study, for biomarker measurements, biopsies of normal-appearing rectal mucosa are being obtained from 1,328 of participants at their 3- or 5-year follow-up colonoscopy. Also, on a subset (n = 112) of these participants, biopsies of normal-appearing rectal mucosa are being taken "non-prep" at randomization, one year post-randomization, and two weeks prior to 3 - 5 year follow-up colonoscopy;and biopsies of normal-appearing mucosa are also being taken from three colon sites (rectum, mid-sigmoid colon, and proximal ascending colon) during follow-up colonoscopies. Enrollment for the "parent" trial is complete and that for the biomarker adjunct study is on schedule. Using biological measurements of risk, as they have for ischemic heart disease, should result in a decline in colorectal cancer incidence and mortality. The proposed project is borne of this vision, and has intertwined missions of investigating the efficacy of two plausible and evidentially well-supported dietary agents, calcium and vitamin D, in modulating a plausible panel of molecular phenotypic biomarkers of risk for colorectal neoplasia, and determining whether this modulation predicts reduced recurrence of colorectal neoplasms.